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EP3054925A1 - A stable pharmaceutical composition containing amlodipine and valsartan - Google Patents

A stable pharmaceutical composition containing amlodipine and valsartan

Info

Publication number
EP3054925A1
EP3054925A1 EP14799323.2A EP14799323A EP3054925A1 EP 3054925 A1 EP3054925 A1 EP 3054925A1 EP 14799323 A EP14799323 A EP 14799323A EP 3054925 A1 EP3054925 A1 EP 3054925A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
amlodipine
production method
valsartan
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP14799323.2A
Other languages
German (de)
French (fr)
Other versions
EP3054925B1 (en
Inventor
Jana SALANDOVA
Lucie Krumbholcova
Tereza VARILOVA
Marketa PRACNA
Lenka KUKACKOVA
Ales BARTUNEK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3054925A1 publication Critical patent/EP3054925A1/en
Application granted granted Critical
Publication of EP3054925B1 publication Critical patent/EP3054925B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a stable pharmaceutical composition containing valsartan and amlodipine, which is in the form of a mono-layer tablet.
  • the patent application WO2000/02543A describes a combined therapy of hypertension with the ATI receptor antagonist (S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoyl-N-[2'(lH-tetrazol-5- yl)biphenyl-4-ylmethyl]amine (valsartan) or its pharmaceutically acceptable salt and the calcium channel blocker 3-ethyl-5-methyl (4RS)-2-[(2-aminoethoxy) methyl] -4-(2-chlorophenyl)-6- methyl-l,4-dihydropyridin-3,5-dicarboxylate (amlodipine) or its pharmaceutically acceptable salt.
  • a fixed combination containing valsartan and amlodipine in one dosage form is described in the patent application WO2007/022113 A.
  • the invention relates to a pharmaceutical composition in the form of a mono-layer tablet in the case of lower doses of valsartan (less than or equal to 160 mg) or bi-layer tablet in the case of higher doses of valsartan (more than 160 mg).
  • the monolayer tablets are prepared by dry granulation (compaction) of a mixture of amlodipine, valsartan and pharmaceutically acceptable excipients, followed by compression into tablets, which can be possibly coated.
  • the bi-layer tablets are prepared by granulation of valsartan, dry or wet granulation of amlodipine; the obtained granules are subsequently individually compressed into a two-layered tablet, which can be possibly coated.
  • Mono-layer tablets containing 320 mg of valsartan and 5 mg of amlodipine were also prepared in accordance with the invention, but in this case bioequivalence was not proved as compared to the mono components. Based on this finding, bi-layer tablets for higher strengths of valsartan (valsartan/amlodipine 320/5 mg and 320/10 mg) were developed.
  • the application WO2009/084003A describes a mono-layer tablet containing a combination of amlodipine and valsartan, which is bioequivalent as compared to the commercially available bi- layer tablet EXFORGE ), but the prepared tablets contain less than 35% by weight of valsartan and therefore tablets containing higher doses of valsartan are too big, which is inconvenient for the patient.
  • the mono-layer tablets in accordance with the invention are prepared by dry granulation of both the active substances together with pharmaceutically acceptable excipients and subsequent compression of obtained granules into mono-layer tablets.
  • a pharmaceutical composition containing valsartan, amlodipine and hydrochlorothiazide is described in the application WO2003/097045A, where individual active substances are preferably separated from each other (kit of parts).
  • the patent application WO2008002905A describes a pharmaceutical composition containing valsartan, amlodipine and hydrochlorothiazide in the form of mono-layer and bi-layer tablets.
  • the mono-layer tablets are prepared by dry granulation (compaction) of a mixture of amlodipine, valsartan, hydrochlorothiazide and pharmaceutically acceptable excipients, the obtained granules are compressed into tablets, which can be possibly coated.
  • a mono-layer tablet containing a combination of amlodipine and valsartan can be prepared that is bioequivalent as compared to the mono components for all the commonly used doses (valsartan/amlodipine 160/5 mg, 160/10 mg, 320/5 mg and 320/10 mg), wherein the tablets of a higher strength have a lower weight compared to commercially available bi-layer tablets (EXFORGE ®), as well as to mono-layer tablets known from the prior art.
  • the invention provides a pharmaceutical composition, having the form of a mono-layer tablet, containing valsartan, amlodipine or their pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition in accordance with the invention optionally contains hydrochlorothiazide as a further active ingredient.
  • the pharmaceutical composition contains valsartan, amlodipine besylate and optionally hydrochlorothiazide as active ingredients.
  • the amount of valsartan in a tablet is from 40 mg to 320 mg, preferably 80 mg, 160 mg and 320 mg; the amount of amlodipine is from 1.25 mg to 20 mg, preferably 2.5 mg, 5 mg and 10 mg; the amount of hydrochlorothiazide is from 5 mg to 50 mg, preferably 12.5 mg and 25 mg.
  • the amount of valsartan in a mono-layer tablet is more than 35% by weight, related to the tablet weight, and it is preferably in a micronized form to improve its biological availability. To ensure compaction of the fine material the wet granulation method has been selected.
  • the pharmaceutical composition in accordance with the invention having the form of a monolayer tablet, contains pharmaceutically acceptable excipients selected from the group consisting of a filler, binder, lubricant, wetting agent, disintegrant and glidant.
  • Suitable fillers are microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, lactitol, fructose, dextrans, sucrose, magnesium carbonate, starch, pre- gelatinized starch.
  • Suitable binders are hydroxypropyl cellulose, hydroxyethyl cellulose, starch, pre-gelatinized starch, polymethacrylates, gelatine, hypromellose, povidone and microcrystailine cellulose.
  • Suitable disintegrants are crospovidone, croscarmellose sodium, starch, pre-gelatinized starch, microcrystailine cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, polacrilin potassium.
  • Suitable wetting agents are sodium lauryl sulfate, polysorbates.
  • Suitable glidants are talc, starch, colloidal silicon dioxide.
  • Suitable anti-adhesives are magnesium stearate, stearic acid, magnesium silicate, calcium stearate, sodium stearyl fumarate, macrogols, hydrogenated vegetable oils, sodium lauryl sulfate.
  • the pharmaceutical agent in accordance with the invention contains:
  • Anti-adhesive agent 0.2 - 2 % by weight
  • the mono-layer tablet in accordance with the invention is optionally provided with a coating.
  • the monolayer tablets in a preferred embodiment contain fillers in the range of 32 to 54.5% by weight, such as microcrystailine cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate, silicified microcrystailine cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, lactitol, fructose, dextrans, sucrose, magnesium carbonate, starch, pre- gelatinized starch.
  • fillers in the range of 32 to 54.5% by weight, such as microcrystailine cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate, silicified microcrystailine cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, lactitol, fructose, dextrans, sucrose, magnesium carbonate, starch, pre- gelatinized starch.
  • lubricants used in the range of 0.2 to 2% by, weight it can be magnesium stearate, stearic acid, magnesium silicate, calcium stearate, sodium stearyl fumarate, macrogols, hydrogenated vegetable oils, sodium lauryl sulfate.
  • Glidants used in the range of 0.1 to 1% by weight, are represented by talc, starch and colloidal silicon dioxide.
  • Binders present in amounts of 2 to 6% by weight, are hydroxypropyl cellulose, hydroxy ethyl cellulose, starch, pre-gelatinized starch, polymethacrylates, gelatine, hypromellose, povidone and microcrystalline cellulose.
  • a disintegrant is selected from the group containing crospovidone, croscarmellose sodium, starch, pre-gelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, polacrilin potassium, usually used in amounts of 1 to 8% by weight.
  • the invention further relates to a production method of a mono-layer tablet containing amlodipine and valsartan.
  • Valsartan together with at least one pharmaceutically acceptable excipient, is granulated by kneading in a granulation device (high shear mixer), or by means of fluidized air (fluidized bed granulator), water being used as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight.
  • a granulation device high shear mixer
  • fluidized air fluidized bed granulator
  • Amlodipine besylate together with at least one pharmaceutically acceptable excipient, is dry granulated, without the use of a wetting agent - i.e. granules are produced either by briquetting, being compressed to solid pieces that are subsequently crushed and sieved to powder.
  • a wetting agent i.e. granules are produced either by briquetting, being compressed to solid pieces that are subsequently crushed and sieved to powder.
  • Another option is the compaction method, where a mixture of the active substance and excipient is compressed between two rollers that rotate in opposite directions and the mixture is compacted by pressure, and subsequently sieved. A force of 3 to 12 kN/cm is used for the compaction.
  • the compaction product of amlodipine is mixed with granules of valsartan and at least one pharmaceutically acceptable excipient, the mixture is homogenized and the tableting blend is compressed to solid pieces - while the obtained cores have the minimum strength of 30 N. After the compression coating is applied on the cores and the tablets are subjected to final drying.
  • the invention further relates to a production method of a mono-layer tablet containing amlodipine, valsartan and hydrochlorothiazide.
  • Valsartan together with at least one pharmaceutically acceptable excipient, is granulated by kneading in a granulation device (high shear mixer), or by means of fluidized air (fluidized bed granulator), water being used as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3%.
  • a granulation device high shear mixer
  • fluidized air fluidized bed granulator
  • Amlodipine besylate together with at least one pharmaceutically acceptable excipient, is dry granulated, without the use of a wetting agent - i.e. granules are produced either by briquetting, being compressed to solid pieces that are subsequently crushed and sieved to powder.
  • a wetting agent i.e. granules are produced either by briquetting, being compressed to solid pieces that are subsequently crushed and sieved to powder.
  • Another option is the compaction method, where a mixture of the active substance and excipient is compressed between two rollers that rotate in opposite directions and the mixture is compacted by pressure, and subsequently sieved. A force of 3 to 12 kN/cm is used for the compaction.
  • the compaction product of amlodipine is mixed with granules of valsartan and hydrochlorothiazide itself, with at least one pharmaceutically acceptable excipient, the mixture is homogenized and the tableting blend is compressed to solid pieces - while cores with the minimum strength of 30 N are obtained. After the compression coating is applied on the cores and the tablets are subjected to final drying.
  • Advantages of the formulation in accordance with the invention clearly include a higher stability resulting from the use of the dry processing method for amlodipine besylate and acceptable values of content uniformity. All dosage forms are produced by the same technology. The achieved stability has confirmed that the selected production technology ensures compatibility of both the active substances. The dosage form is stable even in spite of being a mono -layer tablet where both the active substances get more in contact. The production of mono-layer tablets does not require the use of any special tableting equipment; the production is feasible in conventional tableting machines. Further, the tablet size is very advantageous, especially in terms of patient's compliance.
  • Fig. 1 Dissolution profiles of amlodipine besylate
  • the figures shows the dissolution profiles of three prototypes of amlodipine/valsartan 10/160 mg compared to the original preparation Norvasc ® (another name Istin ® ).
  • Prototype A is slower in both the environments of pH 1.2 and pH 6.8 - amlodipine besylate is released more slowly from the granules. This means that from the dissolution point of view prototypes B and C appear to be suitable.
  • Figures lc and Id compare the higher strength of amlodipine/valsartan compared to the original amlodipine Istin ® .
  • Fig. 2 Dissolution profiles of valsartan
  • the figures show the same trend, i.e. the slowest dissolution profile for prototype B of amlodipine/valsartan 10/160.
  • the profiles are compared to the original valsartan product - Diovan ® . Comparison of the higher strength of 10/320 mg is shown in Figs. 2c and 2d.
  • Fig. 3 Dissolution profile of valsartan after 3M stability testing at pH 6.8
  • Fig. 4 Dissolution profile of valsartan in the triple combination of
  • Figure 4 describes the dissolution profile of valsartan in the triple combination with amlodipine and hydrochlorothiazide.
  • the releasing exhibits the same trend as in the case of the double combination and therefore in the case of this prototype bioequivalence comparable to the original preparation Diovan ® is expected to be proved.
  • Example 1 a mono-layer tablet made of a granulate containing valsartan (wet granulation) powdered amlodipine. The values are quoted in mg.
  • Valsartan together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight.
  • Amlodipine besylate is added to the granulate together with the excipients - the other part of crospovidone, pre-gelatinized starch, calcium carbonate with microcrystalHne cellulose, sodium stearyl fumarate and colloidal silicon dioxide sieved through a sieve with the mesh size of max. 1.0 mm.
  • the tableting blend is compressed to solid pieces with a strength of at least 30 N.
  • the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying.
  • the temperature of the product should not exceed 42°C.
  • Example 2 a mono-layer tablet made of a granulate containing valsartan together with amlodipine (wet granulation). The values are quoted in mg.
  • Coating layer (Macrogol, hypromellose, titanium dioxide, talc, iron oxides) 10.0
  • Valsartan together with amlodipine, sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate, is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3%. Other excipients are added to the granulate - the other part of crospovidone, pre-ge latinized starch, calcium carbonate with microcrystalline cellulose, sodium stearyl fumarate and colloidal silicon dioxide sieved through a sieve with the mesh size of max.
  • the tableting blend is compressed to solid pieces with a strength of at least 30 N.
  • the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying.
  • the temperature of the product should not exceed 42°C.
  • Example 3 a mono-layer tablet made of a granulate containing valsartan (wet granulation) and compacted amlodipine.
  • Microcrystalline cellulose 74.3 Coating layer (Macrogol, hypromellose, titanium dioxide, talc, iron 10.0
  • Valsartan together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight.
  • Amlodipine besylate, together with microcrystalline cellulose, crospovidone, colloidal silicon dioxide and sodium stearyl fumarate is screened through a sieve with the mesh size of 1.0 mm and the mixture is compacted in a compactor.
  • the compacted material is admixed to the granulate together with the remaining excipients - remaining part of crospovidone, pre-gelatinized starch, calcium carbonate with microcrystalline cellulose, sodium stearyl fumarate and colloidal silicon dioxide.
  • the tableting blend is compressed to solid pieces with a strength of at least 30 N.
  • the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying.
  • the temperature of the product should not exceed 42°C.
  • Example 4 a mono-layer tablet made of a granulate containing valsartan (wet granulation) and a granulate containing amlodipine (wet granulation).
  • Coating layer (Macrogol, hypromellose, titanium dioxide, talc, iron 10.0
  • Valsartan, together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent.
  • the mixture is dried to the resulting granulate humidity of 1 to 3% by weight
  • Amlodipine besylate is granulated together with lactose, starch and povidone by kneading with water.
  • the granulate is then dried to achieve the humidity of 1 to 3% by weight.
  • the two granulates are mixed and finally homogenized with the remaining excipients.
  • the tableting blend is compressed to solid pieces with a strength of at least 30 N. After the compression the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying. The temperature of the product should not exceed 42°C.
  • Imp D (A) - impurity D (Amlodipine) - 3-ethyl 5-methyl 2- [(2-aminoethoxy) methyl] ⁇ 4-(2- chlorophenyl)-6-methylpyridine-3, 5-dicarboxylate
  • Imp E (A) - impurity E (Amlodipine) - diethyl (4RS)-2-[(2-aminoethoxy)methyl] -4-(2- chlorophenyl)-6-methyl-l, 4-dihydropyridine-3, 5-dicarboxylate Imp F (A) - impurity F (Amlodipine) - dimethyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2- chlorophenyl)-6-methyl- 1, 4-dihydropyridine-3, 5-dicarboxylate
  • prototype B is the most stable one (Example 3, in which the granulate of amlodipine besylate (prepared by dry granulation - compaction) is admixed to the granulate of valsartan (prepared by wet granulation) together with extragranular excipients; after subsequent homogenization the tableting blend is compressed to solid pieces - cores, which are provided with a coating.
  • Example 3 in which the granulate of amlodipine besylate (prepared by dry granulation - compaction) is admixed to the granulate of valsartan (prepared by wet granulation) together with extragranular excipients; after subsequent homogenization the tableting blend is compressed to solid pieces - cores, which are provided with a coating.
  • mono-layer tablets containing 320 mg of valsartan and 5 mg of amlodipine and 320 mg of valsartan and 10 mg of amlodipine were prepared.
  • Example 5 a mono-layer tablet prepared from a granulate containing valsartan (wet granulation), compacted amlodipine and powdered HCTZ
  • Valsartan together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the required granules the mixture is dried to the resulting granulate humidity of 1-3 to 3%.
  • Amlodipine besylate, together with microcrystalline cellulose, crospovidone, colloidal silicon dioxide and sodium stearyl fumarate is screened through a sieve with the mesh size of 1.0 mm and the mixture is compacted in a compactor.
  • the compacted material is admixed to the granulate together with the remaining excipients - the remaining part of crospovidone, pre-gelatinized starch, calcium carbonate with microcrystalUne cellulose, sodium stearyl fumarate and colloidal silicon dioxide as well as the active ingredient hydrochlorothiazide.
  • the tableting blend is compressed to solid pieces with a strength of at least 30 N.
  • the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 20 mg, the coating process is completed and the tablets are subjected to final drying.
  • the temperature of the product should not exceed 42° C.

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Abstract

The present invention relates to a stable pharmaceutical composition having the form of a mono- layer tablet. The composition contains valsartan, amlodipine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition in accordance with the invention may contain hydrochlorothiazide as further active ingredient.

Description

A stable pharmaceutical composition containing amlodipine and valsartan
Technical Field
The present invention relates to a stable pharmaceutical composition containing valsartan and amlodipine, which is in the form of a mono-layer tablet.
Background Art
The patent application WO2000/02543A describes a combined therapy of hypertension with the ATI receptor antagonist (S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoyl-N-[2'(lH-tetrazol-5- yl)biphenyl-4-ylmethyl]amine (valsartan) or its pharmaceutically acceptable salt and the calcium channel blocker 3-ethyl-5-methyl (4RS)-2-[(2-aminoethoxy) methyl] -4-(2-chlorophenyl)-6- methyl-l,4-dihydropyridin-3,5-dicarboxylate (amlodipine) or its pharmaceutically acceptable salt.
A fixed combination containing valsartan and amlodipine in one dosage form is described in the patent application WO2007/022113 A. The invention relates to a pharmaceutical composition in the form of a mono-layer tablet in the case of lower doses of valsartan (less than or equal to 160 mg) or bi-layer tablet in the case of higher doses of valsartan (more than 160 mg). The monolayer tablets are prepared by dry granulation (compaction) of a mixture of amlodipine, valsartan and pharmaceutically acceptable excipients, followed by compression into tablets, which can be possibly coated. The bi-layer tablets are prepared by granulation of valsartan, dry or wet granulation of amlodipine; the obtained granules are subsequently individually compressed into a two-layered tablet, which can be possibly coated. Mono-layer tablets containing 320 mg of valsartan and 5 mg of amlodipine were also prepared in accordance with the invention, but in this case bioequivalence was not proved as compared to the mono components. Based on this finding, bi-layer tablets for higher strengths of valsartan (valsartan/amlodipine 320/5 mg and 320/10 mg) were developed. The application WO2009/084003A describes a mono-layer tablet containing a combination of amlodipine and valsartan, which is bioequivalent as compared to the commercially available bi- layer tablet EXFORGE ), but the prepared tablets contain less than 35% by weight of valsartan and therefore tablets containing higher doses of valsartan are too big, which is inconvenient for the patient. The mono-layer tablets in accordance with the invention are prepared by dry granulation of both the active substances together with pharmaceutically acceptable excipients and subsequent compression of obtained granules into mono-layer tablets.
A pharmaceutical composition containing valsartan, amlodipine and hydrochlorothiazide is described in the application WO2003/097045A, where individual active substances are preferably separated from each other (kit of parts). The patent application WO2008002905A describes a pharmaceutical composition containing valsartan, amlodipine and hydrochlorothiazide in the form of mono-layer and bi-layer tablets. The mono-layer tablets are prepared by dry granulation (compaction) of a mixture of amlodipine, valsartan, hydrochlorothiazide and pharmaceutically acceptable excipients, the obtained granules are compressed into tablets, which can be possibly coated. It is known from the application WO2007/022113A that dry granulation of active substances and pharmaceutically acceptable excipients does not allow to prepare a mono-layer tablet containing higher doses of valsartan (more than 160 mg) and amlodipine that is bioequivalent to the mono components. A similar problem is also expected in the case of a composition containing valsartan, amlodipine and hydrochlorothiazide, the design of which is not an object of the patent application WO2008002905A.
It has been surprisingly found out that a mono-layer tablet containing a combination of amlodipine and valsartan can be prepared that is bioequivalent as compared to the mono components for all the commonly used doses (valsartan/amlodipine 160/5 mg, 160/10 mg, 320/5 mg and 320/10 mg), wherein the tablets of a higher strength have a lower weight compared to commercially available bi-layer tablets (EXFORGE ®), as well as to mono-layer tablets known from the prior art. It has been further found out that a mono-layer tablet containing a combination of amlodipine, valsartan and hydrochlorothiazide prepared by the method in accordance with the invention is also bioequivalent for all the commonly used doses. Disclosure of Invention
The invention provides a pharmaceutical composition, having the form of a mono-layer tablet, containing valsartan, amlodipine or their pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient. The pharmaceutical composition in accordance with the invention optionally contains hydrochlorothiazide as a further active ingredient.
In a preferable embodiment the pharmaceutical composition contains valsartan, amlodipine besylate and optionally hydrochlorothiazide as active ingredients. The amount of valsartan in a tablet is from 40 mg to 320 mg, preferably 80 mg, 160 mg and 320 mg; the amount of amlodipine is from 1.25 mg to 20 mg, preferably 2.5 mg, 5 mg and 10 mg; the amount of hydrochlorothiazide is from 5 mg to 50 mg, preferably 12.5 mg and 25 mg.
The amount of valsartan in a mono-layer tablet is more than 35% by weight, related to the tablet weight, and it is preferably in a micronized form to improve its biological availability. To ensure compaction of the fine material the wet granulation method has been selected.
In terms of formulation of amlodipine it was necessary to consider stability of the active ingredient itself on one hand and the critical parameter of content uniformity in the final dosage form on the other hand.
The pharmaceutical composition in accordance with the invention, having the form of a monolayer tablet, contains pharmaceutically acceptable excipients selected from the group consisting of a filler, binder, lubricant, wetting agent, disintegrant and glidant.
Suitable fillers are microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, lactitol, fructose, dextrans, sucrose, magnesium carbonate, starch, pre- gelatinized starch. Suitable binders are hydroxypropyl cellulose, hydroxyethyl cellulose, starch, pre-gelatinized starch, polymethacrylates, gelatine, hypromellose, povidone and microcrystailine cellulose.
Suitable disintegrants are crospovidone, croscarmellose sodium, starch, pre-gelatinized starch, microcrystailine cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, polacrilin potassium.
Suitable wetting agents are sodium lauryl sulfate, polysorbates.
Suitable glidants are talc, starch, colloidal silicon dioxide.
Suitable anti-adhesives (lubricants) are magnesium stearate, stearic acid, magnesium silicate, calcium stearate, sodium stearyl fumarate, macrogols, hydrogenated vegetable oils, sodium lauryl sulfate.
The pharmaceutical agent in accordance with the invention contains:
Valsartan 35 - 45 % by weight
Amlodipine 0.5 - 4 % by weight
Filler 32 - 54.5% by weight
Anti-adhesive agent 0.2 - 2 % by weight
Glidant 0.1 - 1 % by weight
Binder 2 - 6 % by weight
Disintegrant 1 - 8 % by weight
Wetting agent 0.2 - 2 % by weight
The mono-layer tablet in accordance with the invention is optionally provided with a coating.
The monolayer tablets in a preferred embodiment contain fillers in the range of 32 to 54.5% by weight, such as microcrystailine cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate, silicified microcrystailine cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, lactitol, fructose, dextrans, sucrose, magnesium carbonate, starch, pre- gelatinized starch. From the group of anti-adhesives (lubricants), used in the range of 0.2 to 2% by, weight it can be magnesium stearate, stearic acid, magnesium silicate, calcium stearate, sodium stearyl fumarate, macrogols, hydrogenated vegetable oils, sodium lauryl sulfate. Glidants, used in the range of 0.1 to 1% by weight, are represented by talc, starch and colloidal silicon dioxide. Binders, present in amounts of 2 to 6% by weight, are hydroxypropyl cellulose, hydroxy ethyl cellulose, starch, pre-gelatinized starch, polymethacrylates, gelatine, hypromellose, povidone and microcrystalline cellulose. A disintegrant is selected from the group containing crospovidone, croscarmellose sodium, starch, pre-gelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, polacrilin potassium, usually used in amounts of 1 to 8% by weight.
The invention further relates to a production method of a mono-layer tablet containing amlodipine and valsartan.
Valsartan, together with at least one pharmaceutically acceptable excipient, is granulated by kneading in a granulation device (high shear mixer), or by means of fluidized air (fluidized bed granulator), water being used as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight.
Amlodipine besylate, together with at least one pharmaceutically acceptable excipient, is dry granulated, without the use of a wetting agent - i.e. granules are produced either by briquetting, being compressed to solid pieces that are subsequently crushed and sieved to powder. Another option is the compaction method, where a mixture of the active substance and excipient is compressed between two rollers that rotate in opposite directions and the mixture is compacted by pressure, and subsequently sieved. A force of 3 to 12 kN/cm is used for the compaction.
The compaction product of amlodipine is mixed with granules of valsartan and at least one pharmaceutically acceptable excipient, the mixture is homogenized and the tableting blend is compressed to solid pieces - while the obtained cores have the minimum strength of 30 N. After the compression coating is applied on the cores and the tablets are subjected to final drying. The invention further relates to a production method of a mono-layer tablet containing amlodipine, valsartan and hydrochlorothiazide.
Valsartan, together with at least one pharmaceutically acceptable excipient, is granulated by kneading in a granulation device (high shear mixer), or by means of fluidized air (fluidized bed granulator), water being used as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3%.
Amlodipine besylate, together with at least one pharmaceutically acceptable excipient, is dry granulated, without the use of a wetting agent - i.e. granules are produced either by briquetting, being compressed to solid pieces that are subsequently crushed and sieved to powder. Another option is the compaction method, where a mixture of the active substance and excipient is compressed between two rollers that rotate in opposite directions and the mixture is compacted by pressure, and subsequently sieved. A force of 3 to 12 kN/cm is used for the compaction.
The compaction product of amlodipine is mixed with granules of valsartan and hydrochlorothiazide itself, with at least one pharmaceutically acceptable excipient, the mixture is homogenized and the tableting blend is compressed to solid pieces - while cores with the minimum strength of 30 N are obtained. After the compression coating is applied on the cores and the tablets are subjected to final drying.
Advantages of the formulation in accordance with the invention clearly include a higher stability resulting from the use of the dry processing method for amlodipine besylate and acceptable values of content uniformity. All dosage forms are produced by the same technology. The achieved stability has confirmed that the selected production technology ensures compatibility of both the active substances. The dosage form is stable even in spite of being a mono -layer tablet where both the active substances get more in contact. The production of mono-layer tablets does not require the use of any special tableting equipment; the production is feasible in conventional tableting machines. Further, the tablet size is very advantageous, especially in terms of patient's compliance. A mono- layer tablet in accordance with the invention containing the maximum used amount of the active substances, i.e. 10 mg of amlodipine and 320 mg of valsartan, only weighs 768 mg, while the weight of the original preparation Exforge® is more than 900 mg.
Brief Description of Drawings
Fig. 1: Dissolution profiles of amlodipine besylate
The figures shows the dissolution profiles of three prototypes of amlodipine/valsartan 10/160 mg compared to the original preparation Norvasc® (another name Istin®). Prototype A is slower in both the environments of pH 1.2 and pH 6.8 - amlodipine besylate is released more slowly from the granules. This means that from the dissolution point of view prototypes B and C appear to be suitable. Figures lc and Id compare the higher strength of amlodipine/valsartan compared to the original amlodipine Istin®.
Fig. 2: Dissolution profiles of valsartan
The figures show the same trend, i.e. the slowest dissolution profile for prototype B of amlodipine/valsartan 10/160. The profiles are compared to the original valsartan product - Diovan®. Comparison of the higher strength of 10/320 mg is shown in Figs. 2c and 2d.
Fig. 3: Dissolution profile of valsartan after 3M stability testing at pH 6.8
All the three developed prototypes A, B and C were loaded for 3 months in the conditions of 40°C and 75% relative humidity. The dissolution profiles got considerably decelerated for prototypes A and C. The figure shows profiles for valsartan, which are more critical in terms of bioequivalence. Prototype B exhibited the most stable formulation.
Fig. 4: Dissolution profile of valsartan in the triple combination of
amlodipine/valsartan/HCTZ
Figure 4 describes the dissolution profile of valsartan in the triple combination with amlodipine and hydrochlorothiazide. The releasing exhibits the same trend as in the case of the double combination and therefore in the case of this prototype bioequivalence comparable to the original preparation Diovan® is expected to be proved.
Examples
Example 1 - a mono-layer tablet made of a granulate containing valsartan (wet granulation) powdered amlodipine. The values are quoted in mg.
Table 1
Valsartan, together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight. Amlodipine besylate is added to the granulate together with the excipients - the other part of crospovidone, pre-gelatinized starch, calcium carbonate with microcrystalHne cellulose, sodium stearyl fumarate and colloidal silicon dioxide sieved through a sieve with the mesh size of max. 1.0 mm. After final homogenization the tableting blend is compressed to solid pieces with a strength of at least 30 N. After the compression the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying. The temperature of the product should not exceed 42°C.
Tablets produced this way had a lower content of amlodipine; repeated experiments proved the same results. Admixing of amlodipine in the extragranular phase is critical; therefore other production methods have been tested, which are described below.
Example 2 - a mono-layer tablet made of a granulate containing valsartan together with amlodipine (wet granulation). The values are quoted in mg.
Table 2
Composition of 1 tbLflm. Prototype A
Valsartan 160.0
Amlodipine besylate 13.9
Silicified microcrystalline cellulose 67.0
Sorbitol 18.5
Calcium carbonate + pre- gelatinized starch 18.5
Pre-gelatinized starch 6.0
Povidone 15.0
Sodium stearyl fumarate 8.0
Sodium lauryl sulphate 2.0
Crospovidone 26.0
Colloidal silicon dioxide 4.0
Coating layer (Macrogol, hypromellose, titanium dioxide, talc, iron oxides) 10.0
Total 348.9 Valsartan, together with amlodipine, sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate, is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3%. Other excipients are added to the granulate - the other part of crospovidone, pre-ge latinized starch, calcium carbonate with microcrystalline cellulose, sodium stearyl fumarate and colloidal silicon dioxide sieved through a sieve with the mesh size of max. 1.0 mm. After final homogenization the tableting blend is compressed to solid pieces with a strength of at least 30 N. After the compression the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying. The temperature of the product should not exceed 42°C.
Example 3 - a mono-layer tablet made of a granulate containing valsartan (wet granulation) and compacted amlodipine.
Table 3
Composition of 1 tbhflm. Prototype B (mg)
Valsartan 160.0
Amlodipine besylate 13.9
Silicified microcrystalline cellulose 67.0
Sorbitol 18.5
Calcium carbonate + pre-gelatinized starch 18.5
Pre-gelatinized starch 6.0
Povidone 15.0
Sodium stearyl fumarate 9,0
Sodium lauryl sulphate 2.0
Crospovidone 36.0
Colloidal silicon dioxide 4.8
Microcrystalline cellulose 74.3 Coating layer (Macrogol, hypromellose, titanium dioxide, talc, iron 10.0
Total 435.0
Valsartan, together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight. Amlodipine besylate, together with microcrystalline cellulose, crospovidone, colloidal silicon dioxide and sodium stearyl fumarate is screened through a sieve with the mesh size of 1.0 mm and the mixture is compacted in a compactor. The compacted material is admixed to the granulate together with the remaining excipients - remaining part of crospovidone, pre-gelatinized starch, calcium carbonate with microcrystalline cellulose, sodium stearyl fumarate and colloidal silicon dioxide. After final homogenization the tableting blend is compressed to solid pieces with a strength of at least 30 N. After the compression the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying. The temperature of the product should not exceed 42°C.
Example 4 - a mono-layer tablet made of a granulate containing valsartan (wet granulation) and a granulate containing amlodipine (wet granulation).
Table 4
Composition of 1 tbl.flm. Prototype C
Valsartan 160.0
Amlodipine besylate 13.9
Silicified microcrystalline cellulose 67.0
Sorbitol 18.5
Calcium carbonate + pre-gelatinized starch 18.5
Pre-gelatinized starch 6.0
Povidone 19,5 Sodium stearyl fumarate 8.0
Sodium lauryl sulphate 2.0
Crospovidone 26.0
Colloidal silicon dioxide 4.0
Lactose monohydrate 34.8
Starch 23.5
Coating layer (Macrogol, hypromellose, titanium dioxide, talc, iron 10.0
Total 411.7
Valsartan, together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the desired granules the mixture is dried to the resulting granulate humidity of 1 to 3% by weight Amlodipine besylate is granulated together with lactose, starch and povidone by kneading with water. The granulate is then dried to achieve the humidity of 1 to 3% by weight. The two granulates are mixed and finally homogenized with the remaining excipients. The tableting blend is compressed to solid pieces with a strength of at least 30 N. After the compression the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 10 mg, the coating is completed and the tablets are subjected to final drying. The temperature of the product should not exceed 42°C.
Comparison of the prototypes
All the three prototypes A, B and C were compared to each other. The tablets were loaded with accelerated conditions - temperature of 40°C and relative humidity of 75%. Critical parameters were monitored, especially purity, content uniformity and dissolution. The results of the tests are shown in Table 5. Table 5: Analytical evaluation of the prototypes
RH - relative humidity
M - month
CU - content uniformity
Imp B (V) - impurity B (Valsartan) - benzyl (2S)-3-methyl-2-[(pentanoyl[[(2'-(lH-tetrazol-5-yl) biphenyl - 4-yIJ methyl] amino] butanoate
Imp D (A) - impurity D (Amlodipine) - 3-ethyl 5-methyl 2- [(2-aminoethoxy) methyl] ~4-(2- chlorophenyl)-6-methylpyridine-3, 5-dicarboxylate
Imp E (A) - impurity E (Amlodipine) - diethyl (4RS)-2-[(2-aminoethoxy)methyl] -4-(2- chlorophenyl)-6-methyl-l, 4-dihydropyridine-3, 5-dicarboxylate Imp F (A) - impurity F (Amlodipine) - dimethyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2- chlorophenyl)-6-methyl- 1, 4-dihydropyridine-3, 5-dicarboxylate
The content and content uniformity are satisfactory for all the prototypes. The change of the preparation method of amlodipine as compared to direct mixing (Example 1) has brought a solution to the problem of content non-uniformity. However, there are perceivable differences between the prototypes in terms of purity. The worst case is prototype A, where both the active substances are granulated together in one step. After three months under the accelerated conditions the content of impurity D increases up to the value of 0.86% by weight. From the purity point of view it is prototype B, where amlodipine besylate is processed using a dry method - compaction, that appears to be the best. Prototype A is not acceptable from the dissolution point of view either. The dissolution profile for amlodipine is considerably slower. In addition, the dissolution profile of valsartan is more critical. It is prototype B that exhibited the best results again. In the case of amlodipine granulation, the production method used for prototypes A and C, the profile of valsartan got considerably slower during the stability tests (Figure No. 3).
According to the results presented in Table 5 prototype B is the most stable one (Example 3, in which the granulate of amlodipine besylate (prepared by dry granulation - compaction) is admixed to the granulate of valsartan (prepared by wet granulation) together with extragranular excipients; after subsequent homogenization the tableting blend is compressed to solid pieces - cores, which are provided with a coating. In a similar way mono-layer tablets containing 320 mg of valsartan and 5 mg of amlodipine and 320 mg of valsartan and 10 mg of amlodipine were prepared. The dissolution profiles shown in Figs. 1 and 2 suggest that the formulation is similar to mono-component products - Diovan and Istin, which was also confirmed in an in-vivo bioequivalence study.
Bioequivalence studies
The combinations of amlodipine/valsartan developed were tested in-vivo, in comparison to mono- component products - Istin® or Norvasc® for amlodipine besylate and Diovan® for valsartan. Table 6: Composition of strengths subjected to in-vivo testing
Table 7: Results of bioequivalence studies
Amlodipine/valsartan 10/160 mg Amlodipine/valsartan 10/320 mg
Amlodipine Valsartan Amlodipine Valsartan
AUC 100.9 % 103.8 % 98 % 97.2 % cmax 98.6 % 109.0 % 100 % 103.1 % Example 5 - a mono-layer tablet prepared from a granulate containing valsartan (wet granulation), compacted amlodipine and powdered HCTZ
Table 8
Valsartan, together with sorbitol, crospovidone, silicified microcrystalline cellulose, povidone and sodium lauryl sulfate is homogenized in a granulator and subsequently granulated by kneading with the use of water as a wetting agent. On achievement of the required granules the mixture is dried to the resulting granulate humidity of 1-3 to 3%. Amlodipine besylate, together with microcrystalline cellulose, crospovidone, colloidal silicon dioxide and sodium stearyl fumarate is screened through a sieve with the mesh size of 1.0 mm and the mixture is compacted in a compactor. The compacted material is admixed to the granulate together with the remaining excipients - the remaining part of crospovidone, pre-gelatinized starch, calcium carbonate with microcrystalUne cellulose, sodium stearyl fumarate and colloidal silicon dioxide as well as the active ingredient hydrochlorothiazide. After final homogenization the tableting blend is compressed to solid pieces with a strength of at least 30 N. After the compression the cores are coated with a hypromellose suspension. When the weight of the cores has increased by 20 mg, the coating process is completed and the tablets are subjected to final drying. The temperature of the product should not exceed 42° C.

Claims

Claims
1. A production method of a mono-layer tablet containing amlodipine and vaisartan or their pharmaceutically acceptable salts, characterized in that
a) vaisartan or its pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable excipient, is granulated with the use of water as a wetting agent,
b) amlodipine or its pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable excipient, is dry granulated,
c) the obtained granules of amlodipine are mixed with the granules of vaisartan and with at least one pharmaceutically acceptable excipient, the mixture is homogenized and the tableting blend is compressed to solid pieces - cores, and
d) the obtained cores are optionally provided with a coating.
2. The production method according to claim 1, characterized in that the mixture of vaisartan and at least one pharmaceutically acceptable excipient according to item a) is wetted with water and the resulting mixture is processed into a granulate by kneading or fluidized granulation.
3. The production method according to claims 1 or 2, characterized in that at least one pharmaceutically acceptable excipient according to item a) is selected irom the group comprising a filler, binder, wetting agent, disintegrant, or any combinations thereof.
4. The production method according to claim 1, characterized in that the dry mixture of amlodipine and at least one pharmaceutically acceptable excipient according to item b) is dry granulated by briquetting or compaction with the use of a force of 3 to 12 kN/cm.
5. The production method according to claims 1 to 4, characterized in that at least one pharmaceutically acceptable excipient according to item a) is selected from the group comprising a filler, disintegrant, glidant, lubricant or any combinations thereof.
6. The production method according to claims 1 to 5, characterized in that the granules of amlodipine are mixed with the granules of valsartan and at least one pharmaceutically acceptable excipient, the mixture is homogenized and the tableting blend is compressed to solid pieces having the minimum strength of 30 N.
7. The production method according to claims 1 to 6, characterized in that at least one pharmaceutically acceptable excipient according to item c) in the extragranular portion is selected from the group comprising a filler, disintegrant, glidant, lubricant or any combinations thereof.
8. The production method according to claims 1 to 7, characterized in that the filler is selected from the group comprising microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, lactitol, fructose, dextrans, sucrose, magnesium carbonate, starch, and pre-gelatinized starch.
9. The production method according to claims 1 to 7, characterized in that the binder is selected from the group comprising hydroxypropyl cellulose, hydroxyethyl cellulose, starch, pre- gelatinized starch, polymethacrylates, gelatine, hypromellose, povidone and microcrystalline cellulose
10. The production method according to claims 1 to 7, characterized in that the wetting agents is selected from the group comprising polysorbates and sodium lauryl sulfate.
11. The production method according to claims 1 to 7, characterized in that the disintegrant is selected from the group comprising crospovidone, croscarmellose sodium, starch, pre-gelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, and polacrilin potassium.
12. The production method according to claims 1 to 7, characterized in that the glidant is selected from the group comprising talc, starch and colloidal silicon dioxide.
13. The production method according to claims 1 to 7, characterized in that the lubricant is selected from the group comprising magnesium stearate, stearic acid, magnesium silicate, calcium stearate, sodium stearyl fumarate, macrogols, hydrogenated vegetable oils, and sodium lauryl sulfate.
14. The production method of the mono-layer tablet according to claims 1 to 13, characterized in that hydrochlorothiazide is further added to the input mixture according to item c) containing granules of valsartan, granules of amlodipine and at least one pharmaceutically acceptable excipient.
15. The production method of the mono-layer tablet according to claim 14, characterized in that hydrochlorothiazide is added freely in the form of powder.
16. A mono-layer tablet, characterized in that it contains valsartan or a pharmaceutically acceptable thereof in an amount of 35 to 45% by weight in the form of granules prepared by wet granulation, amlodipine or a pharmaceutically acceptable salt thereof in an amount of 0.5 to 4% by weight in the form of granules prepared by dry granulation, a filler in an amount of 32 to 54.5% by weight, an antiadhesive agent in an amount of 0.2 to 2% by weight, a glidant in an amount of 0.1 to 1% by weight, a binder in an amount of 2 to 6% by weight, a disintegrant in an amount of 1 to 8% by weight and a wetting agent in an amount of 0.2 to 2% by weight.
17. The mono-layer tablet according to claim 16, characterized in that it further contains 5 to 50 mg of hydrochlorothiazide.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008485A1 (en) * 2017-07-06 2019-01-10 Mankind Pharma Ltd Fixed dose pharmaceutical composition of valsartan and sacubitril

Families Citing this family (10)

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KR101875112B1 (en) * 2015-07-08 2018-07-09 씨제이헬스케어 주식회사 Pharmaceutical Composition Comprising Amlodipine, Valsartan and Rosuvastatin
CN105853418A (en) * 2016-05-23 2016-08-17 上海麦步医药科技有限公司 Composition containing levorotatory amlodipine and azilsartan
CN108567759B (en) * 2018-07-26 2019-06-04 北京百奥药业有限责任公司 A kind of valsartan and Hydrochlorothiade piece and preparation method thereof
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CN112641743B (en) * 2020-12-23 2022-09-02 上海耀大生物科技有限公司 Compound preparation for treating hypertension and preparation process thereof
CN115869272A (en) * 2021-09-29 2023-03-31 北京新领先医药科技发展有限公司 Amlodipine besylate tablet and preparation method thereof
CN114917226A (en) * 2022-03-16 2022-08-19 黄山中皇制药有限公司 Valsartan levamlodipine composition
EP4331586A1 (en) * 2022-08-31 2024-03-06 Adamed Pharma S.A. Anticoagulant therapy with an improved dosage regimen
CN116440132A (en) * 2022-12-20 2023-07-18 福建瑞泰来医药科技有限公司 Medicament containing amlodipine and azilsartan and preparation method thereof
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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9912021A (en) 1998-07-10 2001-04-03 Novartis Ag Novartis Sa Movart Treatment method and pharmaceutical composition
EG24716A (en) 2002-05-17 2010-06-07 Novartis Ag Combination of organic compounds
GT200600371A (en) 2005-08-17 2007-03-21 SOLID DOSE FORMS OF VALSARTAN AND AMLODIPINE AND METHOD TO DO THE SAME
AR061627A1 (en) 2006-06-27 2008-09-10 Novartis Ag SOLID DOSAGE FORMS OF VALSARTAN, AMLODIPINA, AND HYDROCLOROTIAZIDA, AND METHOD FOR PREPARING THEM
MX2010007281A (en) * 2007-12-31 2010-10-05 Lupin Ltd Pharmaceutical compositions of amlodipine and valsartan.

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008485A1 (en) * 2017-07-06 2019-01-10 Mankind Pharma Ltd Fixed dose pharmaceutical composition of valsartan and sacubitril
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
US11819577B2 (en) 2017-07-06 2023-11-21 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril

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EP3054925B1 (en) 2018-07-04
IL244847A0 (en) 2016-05-31
BR112016007414A2 (en) 2017-08-01
JP2016536285A (en) 2016-11-24
WO2015051771A1 (en) 2015-04-16
ZA201601304B (en) 2017-05-31
EA201690679A1 (en) 2016-07-29
PT3054925T (en) 2018-10-30
KR20160058763A (en) 2016-05-25
UA119544C2 (en) 2019-07-10
CZ2013783A3 (en) 2015-04-15
CN105579031A (en) 2016-05-11
ES2689685T3 (en) 2018-11-15
CN105579031B (en) 2018-12-11

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